In pregnant women with sickle cell disease (SCD), placental methylation may be increased, which has been associated with abnormal placental development and other complications, according to a recently published study in PLoS One.

It is well known that pregnancy in women with SCD is linked to increased risk, which may result in placental insufficiency that leads to adverse perinatal outcomes. Although these placental abnormalities have been well reported, their underlying mechanisms remain unclear, including epigenetics.

SCD involves a group of inherited disorders that are differentiated by the presence of hemoglobin S (HbS). The investigators of the current study sought to assess the DNA methylation profile of placentas from women with SCD (HbSS and HbSC genotypes) compared with placentas from women with the HbAA genotype.

The study used the Illumina Methylation EPIC BeadChip to examine whole placental methylation. Pyrosequencing was used to validate data and for real-time quantitative polymerase chain reaction to analyze gene expression.

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Results demonstrated a higher frequency of hypermethylated CpGs sites in the HbSS and HbSC subgroups (73.5% vs 76.2%, respectively) compared with the control group (HbAA). This suggests that the HbSS and HbSC genotypes can modify placental DNA methylation similarly (ie, hypermethylation status) as seen in the common pathophysiology of these SCD subtypes.

A number of differentially methylated regions (DMRs) also demonstrated an elevated hypermethylation status for the HbSS and HbSC subgroups (89.0% vs 86.0%, respectively) compared with methylation data for the control group.

Following analyses among DMRs chosen for validation of methylation (4 DMRs in the HbSS subgroup and 3 in the HbSC subgroup), 3 were validated in the HbSS group, whereas none were validated in the HbSC group. Based on gene expression analysis, differential expression for the PTGFR and GPR56 genes was observed in the HbSS subgroup, as well as for the SPOCK1 and ADCY4 genes in the HbSC subgroup.

These gene expression changes could contribute to abnormal placental development and thus could impact the clinical course, particularly for the fetus, which might result in increased risk for abortion, fetal growth restriction, stillbirth, prematurity, and small-for-gestational-age newborns.

The researchers concluded, “Our results have provided new insights that may head future research [toward] a better understanding of the mechanisms and pathways underlying DNA methylation involvement in the epigenetic regulation of major placental processes in pregnant women with SCD.”

Reference

Gil GP, Ananina G, Maschietto M, et al. Epigenetic analysis in placentas from sickle cell disease patients reveals a hypermethylation profile. PLoS One. 2022;17(9):e0274762. doi:10.1371/journal.pone.0274762